The overall aim of the research is to study the mechanism of anticarcinogenic activity of a number of chemopreventive agents by examining their interaction with a variety of chemical carcinogens and tumor promoting agents in human cell culture systems, using chromosome instability (chromosome breakage and sister chromatid exchange) as the endpoint. The mutational model for cancer etiology, which incudes chromosomal mutation as a possible route, would predict that anticarcinogenic agents would inhibit the mutational activity of carcinogenic chemicals. Several categories of anticarcinogenic chemicals will be studied: (a) phenolic antioxidants, flavonoids, disulfiram, ascorbic acid, selenium, glutathione, and related compounds; (b) retinoids; and (c) protease inhibitors. Cultured skin fibroblasts and peripheral blood lymphocytes from both normal individuals and patients with Fanconi anemia (FA) will be used. FA is an autosomal recessive disorder characterized by a high frequency of spontaneous chromonsome instability, and increased predisposition to malignancy. Although the molecular basis for the syndrome is unknown, there is evidence for defective DNA repair in these cells, and also evidence for defective protection of these cells against the genetic toxicity of oxygen. The cells will be exposed to a variety of carcinogens and tumor promoters, including diepoxybutane, cyclophosphamide, N-ethylnitrosourea, diethylnitrosamine, benzo(a)pyrene, bleomycin, 12-0-tetradecanoylphorbol-13-acetate (TPA), and oxymetholone, in combination with the anticarcinogens to be studied. Studies will be performed with and without a mammalian metabolic activation system, when applicable, using either S-9 mix or an in vivo - in vitro system in which the test chemicals are injected into rats, and the rat serum containing the activated compounds is added to the culture medium. FA cells will also be grown at various oxygen tensions. Comparison of cytogenetic effects of anticarcinogens on the hypersensitive FA cells and normal cells will help clarify the role of free radical scavenging in chemoprevention, as well as the role of modulation of chromosomal mutation.